Targeting a cancer cell Interferon-TBK1 signaling axis attenuates inflammatory memory mediated resistance to immune checkpoint blockade 2257735
TL;DR
It is observed that ex vivo JAKi and TBK1i treatment, in a cancer cell intrinsic manner, induces a more stem-like CD8 T cell response following ICB, possibly through improved interactions with myeloid cells.
Abstract
Acquired resistance in cancer is a major obstacle to durable response after immune checkpoint blockade (ICB). While interferon (IFN) signaling is frequently linked with effective ICB response, prolonged interferon signaling within cancer cells paradoxically drives immune suppression. In preclinical mouse models of ICB, relapsed tumors possess an altered epigenetic landscape characterized by inflammatory memory domain accessibility maintained by STAT1 and IRF3. Here, we restore ICB response by identifying and targeting pathways that maintain IFN-associated memory and resistance. Res 499 tumor cells derived from a late-relapse B16 melanoma were manipulated as indicated, flank-injected into C57BL/6 mice, and treated with ICB. Tumors were harvested on day 16 post-implantation for RNA-seq, ATAC-seq, and flow cytometry. Prolonged exposure of cancer cells to IFN selectively increases the expression of a subset of IFNy stimulated genes, or “memory ISGs”, which are enriched for immune evasive properties. Moreover, persistent IFN signaling induces elevated expression of not only dsRNA-forming endogenous retroelements (EREs), but also of IFN-inducing dsRNA sensors such as MDA5, establishing a STAT1 and IRF3 activating feed-forward loop. Consequently, knock out of MDA5, or pharmacological blockade of IFN and MDA5 signaling via JAK1/2 and TBK1 inhibitors respectively, lowers ERE expression, decreases chromatin accessibility at inflammatory memory loci, and increases ICB sensitivity. Via flow cytometry, we observe that ex vivo JAKi and TBK1i treatment, in a cancer cell intrinsic manner, induces a more stem-like CD8 T cell response following ICB, possibly through improved interactions with myeloid cells. Given emerging clinical data supporting JAK inhibition in ICB-refractory tumors, these findings may suggest additional benefits from targeting TBK1 as well. Combined JAK and TBK1 inhibition attenuates inflammatory memory associated resistance and enhances ICB efficacy. Mark Foundation for Cancer Research Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)